Neoantigen-specific immunity in low mutation burden colorectal cancers of the consensus molecular subtype 4

Background The efficacy of checkpoint blockade immunotherapies in colorectal cancer is currently restricted to a minority of patients diagnosed with mismatch repair-deficient tumors having high mutation burden. However, this observation does not exclude the existence of neoantigen-specific T cells i...

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Published in:Genome medicine Vol. 11; no. 1; pp. 87 - 15
Main Authors: van den Bulk, Jitske, Verdegaal, Els M. E., Ruano, Dina, Ijsselsteijn, Marieke E., Visser, Marten, van der Breggen, Ruud, Duhen, Thomas, van der Ploeg, Manon, de Vries, Natasja L., Oosting, Jan, Peeters, Koen C. M. J., Weinberg, Andrew D., Farina-Sarasqueta, Arantza, van der Burg, Sjoerd H., de Miranda, Noel F. C. C.
Format: Journal Article
Language:English
Published: London BioMed Central 30.12.2019
BioMed Central Ltd
Springer Nature B.V
BMC
Subjects:
Adoptive T cell transfer (ACT)
Antigenic determinants
Antigens
Antigens, Neoplasm - chemistry
Antigens, Neoplasm - immunology
Bioinformatics
Biomedical and Life Sciences
Biomedicine
Blood cells
Bone morphogenetic proteins
Cancer
Cancer immunotherapy
Cancer patients
Cancer Research
Cancer treatment
CD103 antigen
CD8-Positive T-Lymphocytes - cytology
CD8-Positive T-Lymphocytes - metabolism
Colorectal cancer
Colorectal carcinoma
Colorectal Neoplasms - immunology
Colorectal Neoplasms - pathology
Colorectal Neoplasms - therapy
Deoxyribonucleic acid
DNA
DNA Mismatch Repair
DNA-Binding Proteins - genetics
Epitopes
Epitopes - chemistry
Epitopes - immunology
Epitopes - pharmacology
Gene expression
Genetic aspects
Genomes
Health aspects
Human Genetics
Humans
Immune checkpoint
Immunotherapy
Interferon-gamma - metabolism
Low mutation burden
Lymphocytes
Lymphocytes T
Lymphocytes, Tumor-Infiltrating - cytology
Lymphocytes, Tumor-Infiltrating - drug effects
Lymphocytes, Tumor-Infiltrating - metabolism
Medical prognosis
Medicine/Public Health
Metabolomics
Microfilament Proteins - genetics
Mismatch repair
Mismatch repair-proficient (MMR-p)
Mutation
Neoantigens
Patients
Peptides
Peptides - chemical synthesis
Peptides - pharmacology
Pharmacy
Scientific equipment industry
Systems Biology
T cells
T-Lymphocyte Subsets - cytology
T-Lymphocyte Subsets - metabolism
Transcription Factors - genetics
Transforming Growth Factor beta - metabolism
Transforming growth factor-beta
Transforming growth factors
Tumor antigens
Tumor immune microenvironment and immunotherapy
Tumor-infiltrating lymphocytes
Tumors
United States
Netherlands
United States > US
Adoptive T cell transfer (ACT)
Tumor-infiltrating lymphocytes
Mismatch repair-proficient (MMR-p)
CMS
Transforming growth factor-beta
Cancer immunotherapy
Neoantigen
Low mutation burden
ISSN:1756-994X, 1756-994X
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Summary:Background The efficacy of checkpoint blockade immunotherapies in colorectal cancer is currently restricted to a minority of patients diagnosed with mismatch repair-deficient tumors having high mutation burden. However, this observation does not exclude the existence of neoantigen-specific T cells in colorectal cancers with low mutation burden and the exploitation of their anti-cancer potential for immunotherapy. Therefore, we investigated whether autologous neoantigen-specific T cell responses could also be observed in patients diagnosed with mismatch repair-proficient colorectal cancers. Methods Whole-exome and transcriptome sequencing were performed on cancer and normal tissues from seven colorectal cancer patients diagnosed with mismatch repair-proficient tumors to detect putative neoantigens. Corresponding neo-epitopes were synthesized and tested for recognition by in vitro expanded T cells that were isolated from tumor tissues (tumor-infiltrating lymphocytes) and from peripheral mononuclear blood cells stimulated with tumor material. Results Neoantigen-specific T cell reactivity was detected to several neo-epitopes in the tumor-infiltrating lymphocytes of three patients while their respective cancers expressed 15, 21, and 30 non-synonymous variants. Cell sorting of tumor-infiltrating lymphocytes based on the co-expression of CD39 and CD103 pinpointed the presence of neoantigen-specific T cells in the CD39 + CD103 + T cell subset. Strikingly, the tumors containing neoantigen-reactive TIL were classified as consensus molecular subtype 4 (CMS4), which is associated with TGF-β pathway activation and worse clinical outcome. Conclusions We have detected neoantigen-targeted reactivity by autologous T cells in mismatch repair-proficient colorectal cancers of the CMS4 subtype. These findings warrant the development of specific immunotherapeutic strategies that selectively boost the activity of neoantigen-specific T cells and target the TGF-β pathway to reinforce T cell reactivity in this patient group.
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ISSN:1756-994X
1756-994X
DOI:10.1186/s13073-019-0697-8